The goal of this program is to develop and ultimately commercialize small molecule drugs that inhibit cap- dependent translation initiation for the treatment of triple negative (estrogen receptor, progesterone receptor, and HER2 negative) breast tumors with an emphasis on reducing recurrence and increasing survival rates. Unlike other forms of breast cancer, no targeted therapy exists for triple negative tumors. Unfortunately, triple negative breast cancers can be particularly aggressive and more likely to recur than other breast cancer subtypes, resulting in an increased risk of death. A high percentage of triple negative breast tumors have high levels of eIF4E expression and elevated levels of eIF4E have been shown to correlate with higher rates of recurrence and increased risk of death. Because high levels of eIF4E represent high rates of cap-dependent translation;the focus of this proposal is on compounds that selectively inhibit cap-dependent translation of proteins. Therefore, previously identified small molecules that selectively inhibit cap-dependent translation were tested in breast cancer models and lead compounds were selected for further development. In phase I, additional compounds will be synthesized and the correlation between selective cap-dependent translation and inhibition of cancer cell growth evaluated and structure activity relationships developed for cancer growth inhibition. These compounds will be tested on primary fibroblasts, peripheral blood mononuclear cells, and CD34+ cells to determine toxicity to normal cells. Compounds will also be tested in cell based assays for products of cap-dependent translation to help elucidate mechanism of action. Compound synthesis and characterization in the above assays will be performed in an iterative manner until lead candidates are identified. Lead molecules will have at least micromolar activity, minimal toxicity to non-malignant cells, and be stable, amenable to drug development, and novel. Lead compounds will be scaled up and further characterized for pharmacokinetic and safety properties. In vivo efficacy and other IND-enabling pre-clinical studies will be performed in phase II. Resulting drug candidates will provide the first targeted small molecule therapy for triple negative breast cancer. The specific aims for this project are: 1) develop SAR of lead compounds through synthesis and biological testing of 100-150 additional compounds, 2) assess in vitro PK properties, 3) scale up and characterize lead compounds, and 4) determine in vivo PK and safety. PUBLIC HEALTH RELEVANCE: The goal of this program is to develop and ultimately commercialize the first targeted therapy for triple negative breast cancer, which can be particularly aggressive and have a higher rate of recurrence and death than other subtypes of breast cancer.